JPS61259679A - Base agent composition for iontophorese living body electrode - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a base composition for a bioelectrode in iontophoresis.

[Prior art]

Conventionally, the method of administering drugs through the skin has been to apply the drug to the skin along with a base material such as ointment or cream, but in recent years, ionic drugs have once again been infiltrated into the skin using direct current. Iontophoresis (ie, iontophoresis) is gaining popularity.

This method locally administers a drug deep into the skin and is used to treat sterile infections, varicose ulcers, keloids, chronic arthritis, etc., and in recent years has also been used to treat pain.

However, the first problem with this method is the occurrence of burns caused by the electric current. This is said to be caused by poor contact between the metal part of the electrode and the skin, local concentration of current, etc.

The current that causes such burns has a current density of 1 m4/c+A or more.

In order to improve this drawback, Japanese Patent Application Laid-Open No. 55-5276!5 proposes a method of using dampened thick felt and a method of increasing the area of the positive electrode.

Also, JP-A-5. The s-549si was improved by passing a current in the opposite direction at regular intervals.

However, all of these methods have a power consumption of several mA to 1 count mA.
The risk of burns is still unavoidable as current must be used.

In addition, in recent years, new formulation techniques for transdermally administering systemic drugs have been developed, but a method for administering systemic drugs by iontophoresis has not been attempted. This is because iontophoresis was considered to be an inappropriate method for administering systemic drugs because it requires relatively high voltage, high current, and short treatment time to permeate drugs into the body transdermally. be. In particular, it is unsuitable when long-lasting medicine is required. The present inventors have made the following findings as a result of intensive research aimed at realizing transdermal administration of drugs at a controlled rate using low voltage, low current, and long-term treatment. That is, in iontophoresis, transdermal absorption of the drug is achieved at low voltage and low current by blending an ionic drug into a composition consisting of specific polar and non-polar compounds described below and water as a bioelectrode. It was found that this process can be easily carried out.

[Problem that the invention seeks to solve]

The present invention was completed based on two new findings, and its first purpose is to provide a bioelectrode substrate that enables transdermal permeation of drugs at low voltage and low current in iontophoresis. The purpose is to provide the agent composition.

The second object of the present invention is to provide iontophoresis,
The object of the present invention is to provide a method for increasing transdermal permeability of drugs using low voltage and low current.

[Means for solving problems]

That is, the present invention provides at least one polar compound selected from lower alcohols, cyclic ureas, alkylene glycols, and lactam compounds, alcohols having 7 to 20 carbon atoms, and carbon atoms having 5 to 30 carbon atoms optionally substituted with halogens. The present invention relates to a cultivation composition for iontoforese bioelectrodes, which contains at least one nonpolar compound selected from aliphatic hydrocarbons, alcohol esters of aliphatic carboxylic acids having a total of 11 to 26 carbon atoms, and water. .

In this specification, lower alkyl includes methyl, ethyl, propyl, l5o-propyl, n-butyl,
Examples include those having 1 to 4 carbon atoms such as 1so-butyl.

Examples of the polar compounds used in the present invention include the following.

■Lower alcohol: Methyl alcohol, ethyl alcohol, n-propyl alcohol, 1so-propyl alcohol, n-butyl alcohol, 1so-butyl alcohol, 5ec-butyl alcohol, t-butyl alcohol, n-amyl alcohol, 1so-amyl alcohol, Preferred examples include chain monohydric alcohols having 1 to 6 carbon atoms, such as n-hexyl alcohol and cis-3-hexenol.

(iii) Cyclic urea: A 5-membered ring is preferred, and may be substituted with lower alkyl. In particular, -a formula [wherein R, l, R, are each hydrogen or lower alkyl (preferably methyl, ethyl, n-propyl, lso
- a cyclic urea having 1 to 4 carbon atoms such as propyl] is preferred. More specifically, N, N"-
Dimethyl ethylene urea, ethylene urea, N, N'-
Diethylethylene urea and the like are listed.

■Alkylene glycol: The alkylene preferably has 2 to 8 carbon atoms,
Specifically, ethylene glycol, 1,3-propanediol, 1,2-propanediol, butanediol, bentanediol, 2-methyl-2,4-bentanediol, 2-ethyl-I+3=hexanediol, etc. are listed. Ru.

■Lactam compound (■) General formula [In the formula, R3 is a hydrogen atom, lower alkyl (preferably,
Carbons such as methyl, ethyl, n-propyl, 1so-propyl etc. v! , 1 to 3), n is an integer of 3 to 5] Rakum compounds represented by the following are preferred. Specifically 2
-pyrrolidone, N-methylpyrrolidone, N-methylpiperitone, N-methylcaprolactam, and the like.

Examples of the nonpolar compounds used in the present invention include the following.

(alcohol having 7 to 20 carbon atoms) The alcohol may be linear, branched, or cyclic, and may be saturated or unsaturated. Therefore, it also includes terpene alcohols, sesquiterpene alcohols, etc. The alcohols include n-heptyl alcohol, n-decyl alcohol, lauryl alcohol, cetyl alcohol, stearyl alcohol,
1-eicosanol, 2-ethylhexyl alcohol,
2-hexyl alcohol, 2-octyl-dodecyl alcohol, 1so-stearyl alcohol, oleyl alcohol, linalyl alcohol, geranyl alcohol, dimethyl octatool, nerol, citronellol, farnesol, nerolidol, terpineol, mento-
Examples include ole, borneol, and thymol.

(bl 5 to 30 carbon atoms which may be substituted with halogen)
Aliphatic hydrocarbon: The aliphatic hydrocarbon may be linear, branched, or cyclic. Halogen as a substituent is bromine,
Chlor is preferred.

The aliphatic hydrocarbon moiety has 5 carbon atoms in the case of a chain.
An alkyl group having ~30 (preferably 6 to 24) saturated or 1 or 2 unsaturated bonds is preferred,
In the case of a cyclic ring, a monocyclic ring or a bicyclic ring is preferable. In the case of a monocyclic ring, the number of carbon atoms is preferably 6 to 10;
It may be substituted with a saturated or unsaturated alkyl having 1 to 3 carbon atoms, such as the above methyl or a group represented by -C(=CH2)(CH3). Alternatively, two or more monocycles may be bonded via alkylene (eg, methylene, ethylene, etc.). In the case of 2 rings, the number of carbon atoms is 10 to 12
is preferred, which may for example be substituted with one or more lower alkyl such as methyl. Specifically, n-penkune, n-hexane, n-heptane, n-octane,
n-nonane, n-decane, n-undecane, n-dodecane, n-tetradecane, n-hexadecane, n-octadecane, 2-methyl-pencune, 2-methylhexane,
2.3-dimethylhexane, 2-methylnonane, 2.6
- cyclooctane, 2,2,4°4.6.8.8-heptamethylnonane, pliscine, squalane, light liquid paraffin, paramethane, limonene, hydrogenated product of limonene dimer, cyclohexane, ■, 3-dimethylcyclohexane, Examples include cyclooctane, isobutylcyclohexane, cyclododecane, methyldecalin, decalin, octyl bromide, decyl bromide, dodecyl bromide, hexadecyl bromide, dodecyl chloride, dibromododecane, and the like.

(C) Alcohol ester of aliphatic carboxylic acid having a total of 11 to 26 carbon atoms, preferably 19 to 22 carbon atoms - The alcohol moiety is methyl alcohol, ethyl alcohol, n-propyl alcohol, 1so-propyl alcohol, n-
Butyl alcohol, is.

-butyl alcohol, 5ec-butyl alcohol, t-
Butyl alcohol, n-amyl alcohol, is.

- Monohydric alcohols having 1 to 6 carbon atoms such as amyl alcohol and n-hexyl alcohol are listed as preferred. In addition, the carboxylic acid moiety has 18 to 20 carbon atoms.
Among these fatty acids, saturated fatty acids having 18 to 20 carbon atoms are preferred. Specific examples of the ester include methyl stearate, butyl stearate, methyl oleate, ethyl oleate, methyl linoleate, ethyl linoleate, methyl laurate, ethyl laurate, hexyl laurate, isopropyl myristate, Examples include isopropyl valmitate.

The composition weight ratio of polar compounds and non-polar compounds is 99:1
~50:50 or so, and the weight ratio of the sum of the two to water is 99:1 to 40:60, preferably 90:10.
~60:40.

The base composition for an iontophoresis bioelectrode of the present invention can be used as a bioelectrode by itself by incorporating an ion-dissociative drug into it, but it can be held on a drug holding member or the like and then attached to a metal plate. It is preferable to coat it on a conductor such as or put it in a metal container to make a bioelectrode.

Examples of the drug retaining member include impregnated retaining materials, gelling materials, and the like. The impregnating and retaining material may be any material that can be impregnated with and retaining a dissolving agent containing an ionic drug and an absorption enhancer.
For example, nonwoven fabrics, paper, porous membranes, porous ceramics, and foams can be used. In addition, gelling materials include synthetic resins such as polyvinyl alcohol, polyvinyl formal, polyvinylpyrrolidone, polyacrylic acid and its sodium salt, partially saponified polyacrylic esters, polyethylene oxide, and karaya gum, tragacanth gum,
Natural resins such as agar and carrageenan, and partially modified polysaccharides such as hydroxypropylcellulose are used.

The bioelectrode thus obtained can be brought into contact with a living body and connected to a terminal of a normal temperature generator, and by passing an electric current through it, the ion dissociative drug can be infiltrated into the living body.

The drug used in the iontophorase of the present invention is not particularly limited as long as it is an ion dissociative drug and can be exclusively ionized. By using the base composition of the present invention, if the drug is intended for local action, the drug can more easily penetrate deep into the body, and if the drug is intended for systemic action, the drug can more easily penetrate deep into the body. The drug can more easily penetrate into the skin, subcutaneous tissue, and blood. The drug preferably has a molecular weight of 1000 or less, particularly 500 or less.

Specific examples of ionic drugs include the following drugs. Namely, local anesthetics (e.g., tetracaine hydrochloride, procaine hydrochloride, dibucaine hydrochloride, lidocaine hydrochloride, oxyprocaine hydrochloride, diethylaminoethyl valbutylaminobenzoate hydrochloride, pupivacaine hydrochloride, mebihacaine hydrochloride), antihistamines (e.g., diphenhydramine hydrochloride, maleic acid) carbinoxamine, chlorpheniramine maleate, isopentedyl hydrochloride, talemizole hydrochloride), antibiotics [β-lactam antibiotics (e.g. methicillin sodium, oxacillin sodium, cloxacillin sodium, ampicillin sodium, bacampicillin hydrochloride,
Penicillins such as hetacillin potassium and carbenicillin sodium, cephalosporins such as cephalothin sodium, cefazolin sodium, cephapirin sodium, cefazolin sodium, cefametazole sodium, and cefurokidi sodium), oleandomycin phosphate, lincomycin hydrochloride , macrolide antibiotics such as talindamycin hydrochloride, aminoglycoside antibiotics such as fradiomycin sulfate, chloramphenicol sodium succinate, tetracycline hydrochloride, sodium fusidate], chemotherapeutic agents (e.g., isoniacytomethanesulfone) acid sodium, ethambutol hydrochloride), hypnotic/sedative side (e.g. flurazepam hydrochloride) analgesic anti-inflammatory agents (e.g.
diclofenac sodium, sodium salicylate,
benzydamine hydrochloride, ergotamine tartrate, dimethothiazine mesylate), sedatives (e.g. isobrenaline hydrochloride, betahistine mesylate), neuropsychiatric agents (e.g. chlorpromazine hydrochloride, imipramine hydrochloride, amitributyline hydrochloride,
mianserin hydrochloride, doxepin hydrochloride), autonomic nerve agents (
e.g., distigmine bromide), antispasmodics (e.g., atlobin sulfate, butylscopolamine bromide, trospium chloride, pipetanate hydrochloride), antiparkinsonian agents (e.g., piperidine hydrochloride), antiarrhythmic agents (e.g., propranolol hydrochloride, bufetrol hydrochloride, hydrochloric acid) indenolol, dicromol hydrochloride,
Timolol maleate), antihypertensives (e.g., clonidine hydrochloride, hetanidine sulfate, prazosin hydrochloride), coronary vasodilators (e.g., diltiazem hydrochloride, herabamil hydrochloride, trimetazidine hydrochloride), antitussive expectorants (e.g., terbutaline sulfate, hydrochloride) chlorprenaline, bromhexine hydrochloride, tulobuterol hydrochloride, ketotifen fumarate), peptic ulcer treatment agents (e.g. glycopyrronium bromide), adrenal hormone agents (e.g.
hydrocortisone sodium phosphate, dexamethacin sodium, prednisolone sodium phosphate), antineoplastic agents (e.g., lehamizole hydrochloride, pleomycin sulfate,
Examples include pleomycin hydrochloride).

The amount of the ionically dissociative drug added to the base composition of the present invention may be sufficient as long as it exhibits the desired medicinal effect, and it varies depending on the type of drug, patient's weight, symptoms, etc., and depends on these conditions. It may be selected as appropriate. Generally, 0.0 based on the total amount of the bioelectrode base composition of the present invention.
It is preferably 1 to 20% by weight, especially 0.2 to 10% by weight.

The base composition of the present invention may further contain additives used in conventional pharmaceutical preparations, such as various thickeners, gelling agents, excipients, etc., in order to adjust the release of the compounded drug. It's okay.

[Action/Effect]

The bioelectrode base composition of the present invention promotes skin permeation of ion-dissociative drugs by iontophoresis, so even with a low current of about 0.1 to 0.5 mA/ct, skin absorption of the drug can be suppressed. can be achieved.

The base composition used in the present invention promotes the skin permeation of ionic drugs even when no electricity is applied, but when used together with electricity, it synergistically promotes the skin permeation of ionic drugs. Ion introduction is possible even with low current, reducing the risk of burns caused by electricity. Therefore, since the drug can be administered over a long period of time, the drug's efficacy can be sustained. Furthermore, it has become possible to use small batteries, making them portable and emitting light when energized for long periods of time.
There is an advantage that electrical production with controllable dosing is possible.

〔Example〕

EXAMPLES The present invention will be explained in more detail below using Examples, Experimental Examples, etc., but the present invention is not limited by these in any way. Note that in the following, parts indicate parts by weight.

Example 1 1. Clonidine hydrochloride 1 part 2. Distilled water 39 parts 3. N-methylpyrrolidone 45 parts 4. Isopropyl myristate
15 parts Dissolve 1 above in 2, add a mixture of 3 and 4 in advance, and mix and stir. This drug solution 0.4
ml was impregnated into a cotton wool fabric of 20×2Q m* and 211 mm thick, and an aluminum sheet of the same size and 0.2 mm thick was tightly attached to the upper part to form an electrode part.

Comparative Example 1 1. Clonidine hydrochloride 1 part 2. Distilled water 99 parts Dissolve the above 1 in 2,
An electrode was created in the same manner as in Example 1.

Test Example 1 The back of a male Wistar rat (weighing approximately 200 g) was hair removed, and the electrode section of Example 1 or Comparative Example 1 was attached to the right back using adhesive tape.

On the left back, there was an electrode member with the same structure as the drug-containing liquid.
% NaCf solution and attached with adhesive tape as an electrode.

The drug-containing side was used as the anode, and a current of 0.25 mA/c+J was applied for 10 minutes to measure rat tail artery pressure.

The results are shown in Figure 1. The results of Comparative Example 2 were obtained in Example 1 in which no current was applied to the electrode portion.

Example 2 1. Sodium salicylate 10 parts 2. Distilled water 30 parts 3. Ethyl alcohol 45 parts 4. Lauryl alcohol
15 parts A solution was prepared in the same manner as in Example 1, and the diameter was 201.
A polyester nonwoven fabric of 2 mm thick and 2 mm thick was impregnated with 0.5 ml of the solution, and an aluminum current dispersion plate of the same size and 0.5 mm thick was brought into close contact with the nonwoven fabric to form an electrode part.

Comparative Example 3 1, 1-lium salicylate 10 parts 2, and distilled water 90 parts 1 were dissolved in 2 to prepare a solution, which was used as an electrode part in the same manner as in Example 2.

Test Example 2 Rat exfoliated skin was placed on both ends of a glass cell with a diameter of 25 mm and a length of 50 mm with a sampling hole in the center, the electrode part of Example 2 or Comparative Example 3 was attached to one side, and the electrode part of Example 2 or Comparative Example 3 was attached to the other side. Attach the same electrode part as in Example 2 impregnated with Na C# warm solution, use the chemical solution side as the cathode, and apply 0.25 mA.
A current of /cnl was applied for 10 minutes, and the amount of drug permeated through the skin was measured using a high performance liquid chromatograph.

The results are shown in Figure 2. Note that the results of Comparative Example 4 were those in Example 2 in which no current was applied to the electrode portions.

Example 3 1. Diclofenac sodium 1 part 2. Distilled water 49 parts 3. N,N' dimethylethylene urea 40 parts 4. Limonene
10 parts 1 was dissolved in 2, and a solution prepared by previously mixing 4 with 3 was added and mixed to prepare a composition.

Comparative Example 5 A composition was prepared by dissolving 1, 1 part of diclofenac sodium, 2 parts, and 99 parts of distilled water in 2.

Test Example 3 Table 1 shows the results of testing the compositions obtained in Example 3 and Comparative Example 5 for their inhibitory effects on carrageenan foot edema.

In this test, a group of 10 Wistar male rats weighing approximately 200 g were used, and after measuring the volume of each rat's right hind leg, the right hind leg was placed in a 20 mm diameter, deep tube containing the compositions of Example 3 and Comparative Example 5. Sa20. , and a platinum terminal was fixed inside the container to serve as a cathode. In addition, hair was removed from the back, and 20 parts of 5% NaCn solution was applied to a thickness of 20 ws.
The nonwoven fabric of No. 11 was impregnated, the upper part was covered with an aluminum sheet with a thickness of 0.21 mm, and the material fixed with adhesive tape was used as an anode, and a current of 0.5 mA was applied for 20 minutes with a constant current device, and the electrode was removed. After 2 hours, 0.05 ml of 0.5% carrageenan saline was subcutaneously injected into the gyrus area, and 3 hours later, the volume of the right hind leg was measured, and the difference between the previous and right hind leg volumes was determined as the leg edema volume. And so.

Vc-Vt Carrageenin foot edema suppression rate --x 100c However, Vc and Vt represent the average foot edema volumes of the control (drug-free, non-electrifying) group, Example 3, and Comparative Examples 5 and 6, respectively. Note that Comparative Example 6 was prepared by not applying current to the composition obtained in Example 3.

Furthermore, when no current was applied to the electrode portions in Comparative Examples 1, 3, and 5, almost no effect was observed as in each of the Examples.

Table 1 (margin) Examples 4 to 11 1. Sodium salicylate 10 parts 2, distilled water 30 parts 3, polar compound
45 parts 4, non-polar compounds
15 parts A solution was prepared in the same manner as in Example 2 using the polar compounds and non-polar compounds listed in Table 2, and a polyester nonwoven fabric with a diameter of 201 mm and a thickness of 2 mm was impregnated with 0.5 ml of the solution. An aluminum current dispersion plate of the same size and thickness of 0.5 mm was brought into close contact with the nonwoven fabric to form an electrode part.

Test Examples 4 to 11 Tests similar to Test Example 2 were conducted for Examples 4 to 11 to examine the skin permeability of sodium salicylate, and the results are shown in Table 2. This test is 0°25 mA/c
Electricity was applied for 10 minutes at +4, and the transmittance (%) was examined after 4 hours.

The results of Comparative Examples 7 to 14 were obtained by testing the same electrode portions as in Examples 4 to 11 without applying current. (However, Example 4 and Comparative Example 7 are the same as Example 2 and Comparative Example 4, respectively.) Comparative Example 15 is also the same as Comparative Example 3.

[Brief explanation of the drawing]

FIG. 1 and FIG. 2 are graphs showing the effects of the base composition of the present invention, respectively. In FIG. 1, ◯ indicates the sample of Example 1, the opening indicates the sample of Comparative Example 1, and △ indicates the sample of Comparative Example 2. In FIG. 2, ◯ indicates the sample of Example 2, the opening indicates the sample of Comparative Example 3, and △ indicates the sample of Comparative Example 4. Patent Applicant: Nitto Electric Industry Co., Ltd. Proceedings: Written by Masaru Shinbo (spontaneous) December 3, 1985

Claims (1)

[Claims] At least one polar compound selected from lower alcohols, cyclic ureas, alkylene glycols, and lactam compounds, alcohols with 7 to 20 carbon atoms, aliphatic hydrocarbons with 5 to 30 carbon atoms that may be substituted with halogen, total number of carbon atoms 1. A base composition for an iontophoretic bioelectrode, comprising at least one nonpolar compound selected from alcohol esters of 11 to 26 aliphatic carboxylic acids and water.